Adolescent administration of ketamine impairs excitatory synapse formation onto parvalbumin-positive GABAergic interneurons in mouse prefrontal cortex.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.

The impact of preoperative biliary drainage on postoperative healthcare-associated infections and clinical outcomes following pancreaticoduodenectomy: a ten-year retrospective analysis.

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex procedure and easily accompanied by healthcare-associated infections (HAIs). This study aimed to assess the impact of PBD on postoperative infections and clinical outcomes in PD patients. METHODS: The retrospective cohort study were conducted in a tertiary hospital from January 2013 to December 2022. Clinical and epidemiological data were collected from HAIs surveillance system and analyzed. RESULTS: Among 2842 patients who underwent PD, 247 (8.7%) were diagnosed with HAIs, with surgical site infection being the most frequent type (n = 177, 71.7%). A total of 369 pathogenic strains were detected, with Klebsiella pneumoniae having the highest proportion, followed by Enterococcu and Escherichia coli. Although no significant association were observed generally between PBD and postoperative HAIs, subgroup analysis revealed that PBD was associated with postoperative HAIs in patients undergoing robotic PD (aRR = 2.174; 95% CI:1.011-4.674; P = 0.047). Prolonging the interval between PBD and PD could reduce postoperative HAIs in patients with cholangiocarcinoma (≥4 week: aRR = 0.292, 95% CI 0.100-0.853; P = 0.024) and robotic PD (≤2 week: aRR = 3.058, 95% CI 1.178-7.940; P = 0.022). PBD was also found to increase transfer of patients to ICU (aRR = 1.351; 95% CI 1.119-1.632; P = 0.002), extended length of stay (P < 0.001) and postoperative length of stay (P = 0.004). CONCLUSION: PBD does not exhibit a significant association with postoperative HAIs or other outcomes. However, the implementation of robotic PD, along with a suitable extension of the interval between PBD and PD, appear to confer advantages concerning patients' physiological recuperation. These observations suggest potential strategies that may contribute to enhanced patient outcomes.

Association between the triglyceride glucose index and chronic total coronary occlusion: A cross-sectional study from southwest China.

BACKGROUND AND AIM: Insulin resistance (IR) plays an important role in the atherosclerotic process, and the triglyceride glucose (TyG) index is a reliable indicator of IR and is strongly associated with cardiovascular disease. However, there are few studies regarding the relationship between the TyG index and chronic total coronary occlusion (CTO). Herein, the correlation between the TyG index and CTO, as well as their interactions with other traditional cardiovascular risk factors, were investigated. METHODS AND RESULTS: We enrolled 2691 patients who underwent coronary angiography at Guangyuan Central Hospital from January 2019 to October 2021. TyG index results were used to create three groups using the trichotomous method. CTO was defined as complete occlusion of the coronary artery for ≥3 months. Univariate and multivariate logistic regression models, restricted cubic splines, receiver operating characteristic (ROC) curves, and subgroup analyses was performed. A significant correlation between the TyG index and CTO was noted. The risk of CTO was increased 2.09-fold in the group with the highest TyG compared with the lowest (OR, 2.09; 95 % CI, 1.05-4.17; P = 0.036). In addition, there was a linear dose-response relationship between the TyG index and CTO (nonlinear P = 0.614). The area under the ROC curve was 0.643 (95 % CI, 0.572-0.654). Using subgroup analyses, we observed that the TyG index was associated with a significantly higher risk of CTO in males and smokers. CONCLUSIONS: An elevated TyG index was related to the risk of CTO and may constitute a meaningful predictor of CTO, particularly in males and in smokers.

Macrophages exploit the mannose receptor and JAK-STAT1-MHC-II pathway to drive antigen presentation and the antimycobacterial immune response after BCG vaccination.

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M. tb), remains one of the leading causes of fatal infectious diseases worldwide. The only licensed vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), has variable efficacy against TB in adults. Insufficiency of immune cell function diminishes the protective effects of the BCG vaccine. It is critical to clarify the mechanism underlying the antimycobacterial immune response during BCG vaccination. Macrophage mannose receptor (MR) is important for enhancing the uptake and processing of glycoconjugated antigens from pathogens for presentation to T cells, but the roles of macrophage MR in the BCG-induced immune response against M. tb are not yet clear. Here, we discover that macrophage MR deficiency impairs the antimycobacterial immune response in BCG-vaccinated mice. Mechanistically, macrophage MR triggers JAK-STAT1 signaling, which promotes antigen presentation via upregulated MHC-II and induces IL-12 production by macrophages, contributing to CD4 + T cell activation and IFN-γ production. MR deficiency in macrophages reduces the vaccine efficacy of BCG and increases susceptibility to M. tb H37Ra challenge in mice. Our results suggest that MR is critical for macrophage antigen presentation and the antimycobacterial immune response to BCG vaccination and offer valuable guidance for the preventive strategy of BCG immunization.

H-type hypertension is a risk factor for chronic total coronary artery occlusion: a cross-sectional study from southwest China.

BACKGROUND: Chronic total coronary occlusion (CTO) is serious and the "last bastion" of percutaneous coronary intervention. Hypertension and hyperhomocysteinemia (HHCY) are synergistic and significantly increase cardiovascular event risk. The relationship between H-type hypertension and CTO remains unclear; thus, this cross-sectional study investigated this potential association. METHODS: Between January 2018 and June 2022, 1446 individuals from southwest China were recruited to participate in this study. CTO was defined as complete coronary artery occlusion persisting for over three months. H-type hypertension was defined as hypertension with plasma homocysteine levels ≥ 15 µmol/L. Multivariate logistic regression models were applied to assess the association between H-type hypertension and CTO. Receiver operating characteristic (ROC) curves were generated to determine the accuracy of H-type hypertension in predicting CTO. RESULTS: Of the 1446 individuals, 397 had CTO, and 545 had H-type hypertension. After multivariate adjustment, the odds ratio (OR) for CTO in individuals with H-type hypertension was 2.3-fold higher (95% CI 1.01-5.26) than that in healthy controls. The risk of CTO is higher in individuals with H-type hypertension than in those with isolated HHCY and hypertension. The area under the ROC curve for CTO was 0.685 (95% CI, 0.653-0.717) for H-type hypertension. CONCLUSIONS: In southwest China, H-type hypertension is significantly related to the occurrence of CTO. TRIAL REGISTRATION: This retrospective study was registered with the Chinese Clinical Trials Registry ( http://www.chictr.org.cn , ChiCTR2100050519.2.2).

2D Collagen Membranes from Marine Demosponge Chondrosia reniformis (Nardo, 1847) for Skin-Regenerative Medicine Applications: An In Vitro Evaluation.

Research in tissue engineering and regenerative medicine has an ever-increasing need for innovative biomaterials suitable for the production of wound-dressing devices and artificial skin-like substitutes. Marine collagen is one of the most promising biomaterials for the production of such devices. In this study, for the first time, 2D collagen membranes (2D-CMs) created from the extracellular matrix extract of the marine demosponge Chondrosia reniformis have been evaluated in vitro as possible tools for wound healing. Fibrillar collagen was extracted from a pool of fresh animals and used for the creation of 2D-CMs, in which permeability to water, proteins, and bacteria, and cellular response in the L929 fibroblast cell line were evaluated. The biodegradability of the 2D-CMs was also assessed by following their degradation in PBS and collagenase solutions for up to 21 days. Results showed that C. reniformis-derived membranes avoided liquid and protein loss in the regeneration region and also functioned as a strong barrier against bacteria infiltration into a wound. Gene expression analyses on fibroblasts stated that their interaction with 2D-CMs is able to improve fibronectin production without interfering with the regular extracellular matrix remodeling processes. These findings, combined with the high extraction yield of fibrillar collagen obtained from C. reniformis with a solvent-free approach, underline how important further studies on the aquaculture of this sponge could be for the sustainable production and biotechnological exploitation of this potentially promising and peculiar biopolymer of marine origin.

Evaluation and prediction of ecological carrying capacity in the Qilian Mountain National Park, China.

With increasing human impacts on the ecosystem in natural protected areas, there is an urgent need to undertake an assessment of ecological carrying capacity taken as a benchmark for assessing regional sustainability. Based on satellite remote sensing and socio-economic statistical data from 2000 to 2019, this study distinguished the controlling factors for the spatial and temporal patterns of ecological carrying capacity in the Qilian Mountain National Park, one of the 10 pilot national parks in China. The ecological carrying capacity index (ECCI) was developed by using the Driver-Pressure-State-Impact-Response framework and a comprehensive weight method. The results showed that the multiyear averaged ECCI was low in the south and west but was high in central and eastern regions. The spatial distribution of the ECCI was constrained by soil resources, ecosystem quality, land use/cover and water environment. At the regional scale, the ECCI decreased from 2000 to 2014, especially in Tianzhu, where farmland expansion and severe droughts reduced habitat quality and ecosystem function. However, the ECCI increased significantly from 2014 to 2019, which was attributed to a warm moist climate and the implementation of eco-environmental protection policies. Forest and grassland coverage, soil and water conservation, waste water treatment amount and terrestrial water reserves accounted for 35%, 26%, 20% and 8%, respectively, of the temporal variability in the ECCI. Concurrent with national park development, the ECCI is predicted to increase in most areas from 2020 to 2029 by back-propagation artificial neural networks, except for Sunan, Shandan and Menyuan, possibly owing to increasing conflicts between humans and the environment. The findings of this study provide evidence about the effectiveness of government policies in promoting regional sustainability by altering ecosystem composition and function. In addition, the dominant drivers for the temporal variability of ecological carrying capacity varied in space according to stepwise regression analysis, calling for region-specific management strategies in mountain protected areas and their surroundings.

[Effect of Juanbi Qianggu Formula on biological behaviors of fibroblast-like synoviocytes in rheumatoid arthritis by regulating FGFR1 signaling pathway based on network pharmacology and cell function experiments].

This study aimed to explore the molecular mechanism of Juanbi Qianggu Formula(JBQGF), an empirical formula formulated by the prestigious doctor in traditional Chinese medicine, in the treatment of rheumatoid arthritis based on network pharmacology and cell function experiments. The main active components and targets of JBQGF were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and Encyclopedia of Traditional Chinese Medicine(ETCM), and the core targets underwent functional enrichment analysis and signaling pathway analysis. Cytoscape 3.6.0 was used to construct a visualized "active component-target-signaling pathway" network of JBQGF. After screening, nine potential pathways of JBQGF were obtained, mainly including G protein-coupled receptor signaling pathway and tyrosine kinase receptor signaling pathway. As previously indicated, the fibroblast growth factor receptor 1(FGFR1) signaling pathway was highly activated in active fibroblast-like synoviocytes(FLS) in rheumatoid arthritis, and cell and animal experiments demonstrated that inhibition of the FGFR1 signaling pathway could significantly reduce joint inflammation and joint destruction in collagen-induced arthritis(CIA) rats. In terms of the tyrosine kinase receptor signal transduction pathway, the analysis of its target genes revealed that FGFR1 might be a potential target of JBQGF for rheumatoid arthritis treatment. The biological effect of JBQGF by inhibiting FGFR1 phosphorylation was preliminarily verified by Western blot, Transwell invasion assay, and pannus erosion assay, thereby inhibiting matrix metalloproteinase 2(MMP2) and receptor activator of nuclear factor-κB ligand(RANKL) and suppressing the invasion of fibroblasts in rheumatoid arthritis and erosive effect of pannus bone. This study provides ideas for searching potential targets of rheumatoid arthritis treatment and TCM drugs through network pharmacology.

[Effect of 28-day administration of Psoraleae Fructus water extract on early liver injury in rats].

This study aims to investigate the hepatotoxicity of Psoraleae Fructus water extract and the underlying mechanism in rats. Forty-eight rats were randomly assigned into four groups: a blank group and low-(BZGL, 6.25 g·kg~(-1)), medium-(BGZM, 12.5 g·kg~(-1)), and high-dose(BGZH, 25 g·kg~(-1)) Psoraleae Fructus water extract groups. The rats were treated for 28 days, and toxicity and mortality were observed daily. After 28 days, the rats were sacrificed, and the body weight, liver index, and liver-to-brain ratio were calculated. The morphological changes in the liver tissue were observed, and the serum levels of related biochemical indicators were measured. The results showed that compared with the blank group, Psoraleae Fructus water extracts of different doses decreased the body weight, increased the liver index and liver-to-brain ratio, and caused liver hypertrophy and pathological changes. Pathological examination revealed that the rats in Psoraleae Fructus water extract groups had bile duct hyperplasia, inflammatory cell infiltration, and liver cell fibrosis. Compared with the blank group, BGZL elevated the levels of alanine transaminase(ALT), α-glutathione S-transferase(α-GST), and total bile acid(TBA)(P<0.05), and BGZM and BGZH elevated the levels of ALT, TBA, α-GST, γ-glutamyl transferase(γ-GT), purine nucleoside phosphorylase(PNP), ornithine carbamoyltransferase(OCT), and arginase(ArgI)(P<0.05). Compared with the blank group, Psoraleae Fructus water extracts of different doses down-regulated the mRNA and protein levels of bile salt export pump(BSEP) and farnesoid X receptor(FXR) and up-regulated the mRNA and protein levels of tumor necrosis factor-α(TNF-α), nuclear factor kappaB(NF-κB), and cholesterol 7 alpha-hydroxylase(CYP7A1)(P<0.05). The results suggested that Psoraleae Fructus water extract caused toxicity in rats, showing a dose-toxicity relationship. Psoraleae Fructus water extract may cause liver damage, which may be due to its effect on liver bile acid secretion and induction of inflammation.

Roles of Two Major Domains of the Porcine Deltacoronavirus S1 Subunit in Receptor Binding and Neutralization.

Determination of the mechanisms of interspecies transmission is of great significance for the prevention of epidemic diseases caused by emerging coronaviruses (CoVs). Recently, porcine deltacoronavirus (PDCoV) was shown to exhibit broad host cell range mediated by surface expression of aminopeptidase N (APN), and humans have been reported to be at risk of PDCoV infection. In the present study, we first demonstrated overexpression of APN orthologues from various species, including mice and felines, in the APN-deficient swine small intestine epithelial cells permitted PDCoV infection, confirming that APN broadly facilitates PDCoV cellular entry and perhaps subsequent interspecies transmission. PDCoV was able to limitedly infect mice in vivo, distributing mainly in enteric and lymphoid tissues, suggesting that mice may serve as a susceptible reservoir of PDCoV. Furthermore, elements (two glycosylation sites and four aromatic amino acids) on the surface of domain B (S1B) of the PDCoV spike glycoprotein S1 subunit were identified to be critical for cellular surface binding of APN orthologues. However, both domain A (S1A) and domain B (S1B) were able to elicit potent neutralizing antibodies against PDCoV infection. The antibodies against S1A inhibited the hemagglutination activity of PDCoV using erythrocytes from various species, which might account for the neutralizing capacity of S1A antibodies partially through a blockage of sialic acid binding. The study reveals the tremendous potential of PDCoV for interspecies transmission and the role of two major PDCoV S1 domains in receptor binding and neutralization, providing a theoretical basis for development of intervention strategies. IMPORTANCE Coronaviruses exhibit a tendency for recombination and mutation, which enables them to quickly adapt to various novel hosts. Previously, orthologues of aminopeptidase N (APN) from mammalian and avian species were found to be associated with porcine deltacoronavirus (PDCoV) cellular entry in vitro. Here, we provide in vivo evidence that mice are susceptible to PDCoV limited infection. We also show that two major domains (S1A and S1B) of the PDCoV spike glycoprotein involved in APN receptor binding can elicit neutralizing antibodies, identifying two glycosylation sites and four aromatic amino acids on the surface of the S1B domain critical for APN binding and demonstrating that the neutralization activity of S1A antibodies is partially attributed to blockage of sugar binding activity. Our findings further implicate PDCoV's great potential for interspecies transmission, and the data of receptor binding and neutralization may provide a basis for development of future intervention strategies.

Beneficial effects of metformin supplementation in hypothalamic paraventricular nucleus and arcuate nucleus of type 2 diabetic rats.

Background Oxidative stress and inflammation play important roles in the development of diabetes. Metformin (MET) is considered as the first-line therapy for patients with type 2 diabetes (T2D). Hypothalamic paraventricular nucleus (PVN) and hypothalamic arcuate nucleus (ARC) are vital in obesity and diabetes. However, there have been few studies on the effects of MET on inflammatory reaction and oxidative stress in the PVN and ARC of T2D diabetic rats. Methods Male Sprague-Dawley (SD) rats were fed with high-fat diet (HFD), and intraperitoneally injected with low-dose streptozotocin (STZ, 30 mg/kg) at 6th week to induce T2D diabetes. After injection of STZ, they were fed with HFD continually. Starting from the 8th week of HFD feeding, T2D rats received intragastrical administration of MET (150 mg/kg/day) in addition to the HFD for another 8 weeks. At the end of the 15th week, the rats were anaesthetized to record the sympathetic nerve activity and collect blood and tissue samples. Results In comparison with control rats, T2D diabetic rats had higher levels of pro-inflammatory cytokines (PICs) and excessive oxidative stress in the PVN and ARC, accompanied with more activated astrocytes. The renal sympathetic nerve activity (RSNA) and the plasma norepinephrine (NE) increased in T2D diabetic rats. The expression of tyrosine hydroxylase (TH) increased and the expression of 67-kDa isoform of glutamate decarboxylase (GAD67) decreased in T2D diabetic rats. Supplementation of MET decreased blood glucose, suppressed RSNA, decreased PICs (TNF-α, IL-1ß and IL-6) in PVN and ARC, attenuated oxidative stress and activation of astrocytes in ARC and PVN of T2D diabetic rats, as well as restored the balance of neurotransmitter synthetase. The number of Fra-LI (chronic neuronal excitation marker) positive neurons in the ARC and PVN of T2D diabetic rats increased. Chronic supplementation of MET also decreased the number of Fra-LI positive neurons in the ARC and PVN of T2D diabetic rats. Conclusion These findings suggest that the PVN and ARC participate in the beneficial effects of MET in T2D diabetic rats, which is possibly mediated via down-regulating of inflammatory molecules, attenuating oxidative stress and restoring the balance of neurotransmitter synthetase by MET in the PVN and ARC.

PE_PGRS: Vital proteins in promoting mycobacterial survival and modulating host immunity and metabolism.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), is the leading infectious cause of mortality worldwide. One of the key reasons for M. tb pathogenesis is the capability of M. tb to evade immune elimination and survive in macrophage, eventually causing chronic infection. However the pathogenicity mechanism of M. tb is not unclear yet, and thus diagnosis and therapy for TB remains a challenge. The genome of M. tb, encodes a unique protein family known as the PGRS family, with largely unexplored functions. Recently, an increasing number of reports have shown that the PE_PGRS proteins play critical roles in bacterial pathogenesis and immune evasion. The PE_PGRS protein family, characterized by a special N-terminal PE (Pro (P)-Glu (E) motif) domain and a C-terminal PGRS (Polymorphic GC-rich Repetitive Sequences) domain, is restricted mainly to pathogenic mycobacteria. Here we summarize current literature on the PE_PGRS as vital proteins in promoting bacterial survival and modulating host immunity, cell death and metabolism. We also highlight the potential of PE_PGRS as novel targets of anti-mycobacterial interventions for TB control.

Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors.

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.

PTEN loss confers sensitivity to rapalogs in clear cell renal cell carcinoma.

Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.

BAP1 loss augments sensitivity to BET inhibitors in cancer cells.

The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.

Dyadic effects of rumination and self-disclosure on posttraumatic growth in newly diagnosed gynecological cancer couples: an actor-partner interdependence modeling approach.

OBJECTIVE: To examine the dyadic effects of rumination and self-disclosure on posttraumatic growth among newly diagnosed gynecological cancer couples. METHODS: This cross-sectional study recruited 400 newly diagnosed gynecological cancer couples from a tertiary general hospital from July to December 2020. Questionnaires were administered to collect information on demographic and cancer-related characteristics, rumination, self-disclosure, and posttraumatic growth. The actor-partner interdependence model was used to explore the dyadic effects of rumination and self-disclosure on posttraumatic growth. RESULTS: Gynecological cancer survivors reported more posttraumatic growth than their spouses. The patients' deliberate rumination and self-disclosure and spouses' self-disclosure had actor and partner effects on their own and their spouses' posttraumatic growth. Besides, the patients' intrusive rumination and spouses' deliberate rumination had actor effects on their own posttraumatic growth. CONCLUSIONS: Spouses' posttraumatic growth was influenced by their own and their wives' deliberate rumination and self-disclosure, while survivors' posttraumatic growth was affected by their own deliberate rumination, intrusive rumination, self-disclosure, and their spouses' self-disclosure. Promoting deliberate rumination and self-disclosure could facilitate the couples' posttraumatic growth. Besides, reducing intrusive rumination may be useful for the survivors and indirectly contribute to spouses' posttraumatic growth. This study indicates that couple-centered interventions may be crucial and more effective in facilitating posttraumatic growth among newly diagnosed gynecological cancer couples.

A Novel Imidazolinone Derivative with 5-Arylidene and 2-Substituted Mercapto Group as Potent Anti-Hepatitis C Virus Compound.

Here six novel imidazolinone derivatives have been synthesized and the compound 4b containing 5-para-methoxy-phenylidene and 2-thioalkylation terminal substitution with 3'-cyano-2',6'-dimethylphenyl showed the best anti-HCV activity and the lowest cytotoxicity. Selectivity index (SI=CC50 /IC50 ) for the 4b was determined as 36, indicating that compound 4b was highly selective towards HCV.

Facile Solution-Refluxing Synthesis and Photocatalytic Dye Degradation of a Dynamic Covalent Organic Framework.

Covalent organic frameworks (COFs), as a novel crystalline porous adsorbent, have been attracting significant attention for their synthesis and application exploration due to the advantages of designability, stability, and functionalization. Herein, through increasing the concentration of the acid catalyst, a facile solution-refluxing synthesis method was developed for the preparation of a three-dimensional dynamic COF material, COF-300, with high yields (>90%) and high space−time yields (>28 kg m−3 day−1). This synthesis method not only permits gram-scale synthesis, but also yields products that well maintain porosity and unique guest-dependent dynamic behavior. Moreover, the catalytic activity of COF-300 as a metal-free photocatalyst was explored for the first time. Under 365 nm ultra-violet light irradiation, COF-300 can effectively catalyze the dye degradation (>99%) in wastewater with good recyclability. By adding magnetic Fe3O4 nanoparticles into the solution-refluxing synthesis of COF-300, Fe3O4/COF-300 nanocomposites can be obtained and used as magnetically recyclable photocatalysts, demonstrating the superiority of this facile synthesis procedure. Our study provides new insights for the preparation of COF materials and a constructive exploration for their water treatment application.

Development of Near-Infrared Nucleic Acid Mimics of Fluorescent Proteins for In Vivo Imaging of Viral RNA with Turn-On Fluorescence.

GFP-like fluorescent proteins and their molecular mimics have revolutionized bioimaging research, but their emissions are largely limited in the visible to far-red region, hampering the in vivo applications in intact animals. Herein, we structurally modulate GFP-like chromophores using a donor-acceptor-acceptor (D-A-A') molecular configuration to discover a set of novel fluorogenic derivatives with infrared-shifted spectra. These chromophores can be fluorescently elicited by their specific interaction with G-quadruplex (G4), a unique noncanonical nucleic acid secondary structure, via inhibition of the chromophores' twisted-intramolecular charge transfer. This feature allows us to create, for the first time, FP mimics with tunable emission in the near-infrared (NIR) region (Emmax = 664-705 nm), namely, infrared G-quadruplex mimics of FPs (igMFP). Compared with their FP counterparts, igMFPs exhibit remarkably higher quantum yields, larger Stokes shift, and better photostability. In a proof-of-concept application using pathogen-related G4s as the target, we exploited igMFPs to directly visualize native hepatitis C virus (HCV) RNA genome in living cells via their in situ formation by the chromophore-bound viral G4 structure in the HCV core gene. Furthermore, igMFPs are capable of high contrast HCV RNA imaging in living mice bearing a HCV RNA-presenting mini-organ, providing the first application of FP mimics in whole-animal imaging.

Prostate cancer cells survive anti-androgen and mitochondrial metabolic inhibitors by modulating glycolysis and mitochondrial metabolic activities.

BACKGROUND: Most cancer cells are more glycolytic even under aerobic conditions compared with their normal counterparts. Recent evidence of tumor cell metabolism, however, shows that some tumors also increase mitochondrial oxidative phosphorylation (ox-phos) at some disease states during progression and/or development of drug resistance. Our data show that anti-androgen enzalutamide (ENZA) resistant prostate cancer (PCa) cells use more mitochondrial metabolism leading to higher ox-phos as compared to the ENZA-sensitive cells and can become vulnerable to mitochondrial metabolism targeted therapies. METHODS: Seahorse assay, mass spectrometry and high resolution fluorescence confocal microscopy coupled with image analysis has been used to compare mitochondrial metabolism in ENZA-treated and -untreated anti-androgen-sensitive LNCaP and -resistant C4-2, CWR22ν1, and PCa2b cells. Ex vivo fluorescence microscopy and image analysis has been standardized to monitor mitochondrial electron transport (ETS) activity that likely increases ox-phos in circulating tumor cells (CTCs) isolated fom patients undergoing AR-targeted therapies. RESULTS: Our data show that PCa cells that are resistant to anti-androgen ENZA switch from glycolysis to ox-phos leading to an increased ETS activity. ENZA pretreated cells are more vulnerable to ETS component complex I inhibitor IACS-010759 (IACS) and mitochondrial glutaminase inhibitor CB-839 that reduces glutamate supply to tricarboxylic acid cycle. CTCs isolated from 6 of 20 patient blood samples showed relatively higher ETS activity than the rest of the patients. All six patients have developed ENZA resistance within less than 6 months of the sample collection. CONCLUSION: The enhanced growth inhibitory effects of mitochondrial metabolic inhibitors IACS and CB-839 in ENZA pretreated PCa cells provides a rationale for designing a drug combination trial. Patients can be selected for such trials by monitoring the mitochondrial ETS activities in their CTCs to maximize success.